Omentin Protects Against LPS-induced Ards Through Suppressing Pulmonary Inflammation And Promoting Endothelial Barrier Via An Akt/eNOS-dependent Mechanism

Background and Objective:ARDS is characterized by an increased pulmonary inflammatory response and endothelial barrier permeability.As a novel adipokine that links inflammation and obesity,omentin has been shown to benefit obesity-related systemic vascular diseases;however,its effects on ARDS are largely unknown.We hypothesized that omentin protects against ARDS by suppressing pulmonary inflammation and promoting endothelial barrier.Methods: Circulating omentin and biomarkers in patients with ARDS were assessed to appraise the clinical significance of omentin in ARDS.Mice were subjected to systemic administration of adenoviral vector expressing omentin(Ad-omentin)and treatment of recombinant human omentin(rh-omentin)to examine its effects in LPS-induced ARDS.Cultured pulmonary endothelial cells were treated with rh-omentin to further investigate its underlying mechanism.Results:1.Compared with the healthy controls,the plasma omentin levels were lower in patients with ARDS.Compared with the nonsurvivors,the survivors maintained higher concentrations of omentin.Moreover,higher omentin levels were observed in mild ARDS patients.A decreased level of circulating omentin was negatively correlated with WBC and PCT in patients with ARDS.However,there were no correlations between the circulating omentin and the duration of ventilation,the length of respiratory intensive care unit(RICU)stay or hospital stay in patients with ARDS2.Ad-omentin protected against the LPS-induced ARDS by alleviating the pulmonary inflammatory response and endothelial barrier injury,decreasing the pulmonary microvascular hyper-permeability and increasing the levels of ?-catenin and VE-cadherin in mice.3.After LPS insult,treatment of pulmonary endothelial cells with rh-omentin attenuated pulmonary inflammatory response and microvascular hyper-permeability by restoring adherens junctions and cytoskeleton organization,suppressing endothelial cell apoptosis and reducing levels of cleaved caspase-3,meanwhile,promoted EC differentiation with no significant alternation in EC migration.4.Omentin activates Akt-related signaling pathways in vivo and in vitro.Moreover,omentin-mediated enhancement of endothelial cell survival and differentiation was blocked by inactivation of the Akt/eNOS pathway with the use of LY294002 and L-NAME.Conclusion:We demonstrate that omentin protects against LPS-induced ARDS by suppressing inflammation and promoting the pulmonary endothelial barrier,at least partially,through an Akt/eNOS-dependent mechanism.Therapeutic strategies aiming to restore omentin levels may be valuable for the prevention or treatment of ARDS.